The National
Center for Advancing Translational Sciences (NCATS) seeks to develop a therapeutics
discovery pilot program that will explore new therapeutic uses for
proprietary drug candidates (Agents) across a broad range of human diseases.
This innovative program will match Agents and associated data from
pharmaceutical company partners with the best ideas for new therapeutic uses
from the biomedical research community.

PAR-12-203 encourages X02 pre-applications for the NIH-Industry Pilot Program:
Discovering New Therapeutic Uses for Existing Molecules. The X02
pre-application is the first step in the application process for RFA-TR-12-004 and RFA-TR-12-005; applicants must read both of the companion FOAs. The X02
pre-applications will be evaluated by outside scientific experts.

Investigators whose X02 pre-applications are judged to be
the most meritorious will be notified of the opportunity to submit a UH3
application under this FOA or a UH2/UH3 application under RFA-TR-12-004.

The UH3 will support milestone-driven Phase IIa proof of
concept trials to assess the potential clinical efficacy of an Agent, made
available for this program by the pharmaceutical partners, for its potential
new use in the proposed disease population. The project period for the UH3
is up to two years.

Key Dates

Posted Date

June 12, 2012

Open Date (Earliest Submission Date)

November 17, 2012

Letter of Intent Due Date

Not Applicable

Application Due Date(s)

December 17, 2012, by 5:00 PM local time of applicant
organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

March 2013

Advisory Council Review

May 2013

Earliest Start Date(s)

June 2013

Expiration Date

December 18, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide, except where instructed to do otherwise
(in this FOA or in a Notice from the NIH Guide for Grants and
Contracts). Conformance to all requirements (both in the
Application Guide and the FOA) is required and strictly enforced. Applicants
must read and follow all application instructions in the Application Guide as
well as any program-specific instructions noted in Section IV. When the program-specific
instructions deviate from those in the Application Guide, follow the
program-specific instructions. Applications that do not comply with
these instructions may be delayed or not accepted for review.

In April 2011, NIH convened an NIH-Industry
Roundtable that included a group of senior leaders and experts from the
pharmaceutical industry, government, academia, and the non-profit sector to
explore opportunities to foster new NIH-industry partnerships that facilitate
drug rescue and repurposing. Some of the challenges that were identified
include: resource implications (the time and resources for a pharmaceutical
company to maintain, update, and organize their compound libraries for drug
rescue and repurposing); patent considerations (off-patent compounds or
compounds whose patents are close to expiring, may not be attractive to
industry because the financial return and market incentives for the product may
be limited); and transactional hurdles related to developing, negotiating and
implementing appropriate legal agreements among the parties, including
addressing such concerns as intellectual property rights and liability. The
Roundtable participants agreed that more can and should be done to increase
engagement and partnerships in drug rescue and repurposing and to enhance the
success of these efforts. In response to one of the recommendations from the meeting,
NCATS has developed an NIH-Industry Pilot Program: Discovering New Therapeutic
Uses for Existing Molecules.

This Program will
fund research to identify new therapeutic uses of proprietary drug candidates (compounds
and biologics), made available by pharmaceutical company partners, to benefit
public health. NCATS is especially interested in projects that address areas
of unmet medical need. NCATS plans to initiate the research program as a pilot
with a limited set of high-quality drug candidates (Agents)
contributed by the pharmaceutical company partners. If the pilot is
successful, the Program may be expanded to include additional pharmaceutical or
biotechnology company partners, Agents, and new therapeutics discovery projects.

Research
Objectives

The Program intends to support innovative ideas from the
biomedical research community for the discovery of potential therapeutic uses
of these Agents in previously unexplored disease areas. Proof of concept studies can include,
as examples, use of an Agent as a stand-alone intervention or as an adjunctive
intervention (if there is no evidence of drug-drug interactions with the
proposed standard of care treatment). Strategies to inform the selection of
patients for proposed new uses of the Agents are of interest.

For this FOA, Phase IIa proof of concept trials are defined
as studies designed to explore new hypotheses and to assess whether the Agent
demonstrates an early signal of efficacy in the targeted patient population,
typically 150 subjects or less. In addition to clinical benefit, Phase IIa
trials also include assessments of safety, tolerability, and PD/PK response of
the Agent.

UH3
objectives

The UH3 activities will include exploratory, phase IIa proof
of concept trials designed to establish the relationship between the magnitude
and duration of target modulation and clinical efficacy of the Agent in the
proposed disease population. The inclusion of biomarkers in the design of the
study is encouraged, when appropriate: e.g., the inclusion of PK/PD biomarkers
to assess target engagement, exposure and functional pharmacological activity
of the Agent (see, Morgan P., et. al, Drug
Discov. Today (2012), doi:10.1016/j.drudis.2011.12.020), or the use of
molecular markers of disease, pharmacogenomics, or other biomarkers as patient
selection strategies. The goals of the Phase IIa proof of concept trials are to
determine that the Agent modulates the target/mechanism and shows potential for
efficacy in the proposed disease population, thereby de-risking further
clinical development of the Agent for a new therapeutic use that has not
previously been explored. The duration of the UH3 project period is up to two
years.

In cases where the proof of concept studies are successful,
it is anticipated that the pharmaceutical company partner will pursue further clinical
development of the Agent for the new therapeutic use, including requisite Phase
III clinical trials, ultimately commercializing the novel therapeutic
intervention for the new disease indication whenever feasible.

Application
Process

The submission of an X02 pre-application is a necessary
first step in applying for an award under this FOA or the companion FOA, RFA-TR-12-004 (UH2/UH3); applicants must also read both companion FOAs prior to submitting an
X02 pre-application. Pre-applications submitted in response PAR-12-203 will be evaluated by outside scientific experts. X02 applicants will
receive feedback on the scientific merit, technical feasibility, administration
and management plans, and overall potential for
impact of the science proposed in the pre-application Investigators
whose X02 pre-applications are identified as being highly meritorious
and relevant to program priorities will be notified of the opportunity to
submit a UH3 application.

X02 applicants invited to submit a UH3 application must
contact the pharmaceutical company partner for the Agent that was selected for
studies in the X02 pre-application, and execute an appropriate Confidential
Disclosure Agreement (see template CDAs). Under the CDA, the applicant and pharmaceutical
company partner will exchange confidential information (e.g., additional
information on the Agent and studies to test the proposed new therapeutic use
of the Agent), as deemed necessary, to initiate discussions. Subsequently, it
is anticipated that a Collaborative Research Agreement (CRA)
between the applicant and the pharmaceutical company partner will be the
vehicle through which the applicant obtains permission to work with the Agent
on the research project plan for the UH3 application. The applicant must
provide the NIH with documentation of access to the Agent and associated data needed
for filing an investigator-sponsored Investigational New Drug (IND) Application
and for conducting the proposed clinical trial (e.g., an executed CRA).

Partnership
Information

A key component of this FOA is the formation of
collaborative partnerships between the biomedical research community and
industry partners.
NCATS has executed a Memorandum of Understanding (MOU)
with each of the pharmaceutical company partners to provide a framework under
which specific proprietary Agents will be provided by these partners to the
program awardees. Template agreements have been developed for this program: Confidential
Disclosure Agreements (CDAs) and Collaborative Research Agreements (CRAs)
between the pharmaceutical company partner and the applicant. These template
agreements have been developed to streamline interactions among the parties for
the Program, and it is anticipated that applicants will use the agreements. Investigators
should work with their institutional technology transfer or sponsored research
office to finalize the terms and conditions of the CDA and CRA for the selected
Agent prior to submission of a UH3 application. A successful UH3 application
will be contingent on the applicant’s ability to provide the NIH with
documentation of access to the selected Agent and associated data needed for
filing an investigator-sponsored IND in order to conduct the proposed clinical
trials (e.g., an executed CRA or letter from the pharmaceutical partner).

Notification of opportunity to submit a full UH2/UH3 or
UH3 application

December 17 2012

Submission date for UH2/UH3 applications

March 2013

Scientific merit review for UH2/UH3 applications

May 2013

NCATS Advisory Council review of applications

July 2013

Earliest possible start date for awarded grants

Section II. Award Information

Funding Instrument

Cooperative Agreement

Application Types Allowed

New

The OER
Glossary and the SF 424 (R&R) Application Guide provide details on
these application types.

Funds Available and Anticipated Number of Awards

NCATS intends to commit up to $20 million in FY 2013 to fund
six to eight UH2/UH3 or UH3 awards in response to this FOA and the companion
FOA (RFA-TR-12-004).
Future year amounts will depend on annual appropriations.

Award Budget

Application budgets are not limited, but need to reflect
actual needs of the proposed project.

Award Project Period

The total project period for a UH3 application submitted
in response to this FOA may not exceed two years.

NIH grants policies as
described in the NIH Grants
Policy Statement will apply to the applications
submitted and awards made in response to this FOA.

Section III. Eligibility
Information

1. Eligible Applicants

Eligible Organizations

This FOA is a limited competition for those applicants who
submitted a pre-application in response to PAR-12-203 [X02] and have been notified of the opportunity to submit a UH3 application.

Foreign Institutions

Not Applicable.

Required Registrations

Applicant organizations must complete the following
registrations as described in the SF 424 (R&R) Application Guide to be
eligible to apply for or receive an award. Applicants must have a valid Dun and
Bradstreet Universal Numbering System (DUNS) number in order to begin each of the
following registrations.

All Program Directors/Principal Investigators (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director/Principal
Investigator)

This FOA is a limited competition for those applicants who
submitted an X02 pre-application in response to PAR-12-203 [X02] and have been notified of the opportunity to submit a UH3 application.

For these UH3 applications, the PD/PI must be the same PD/PI
listed on the X02 pre-application. For UH3 applications proposing multiple PD(s)/PI(s),
the contact PD/PI must be the same PD/PI listed as the contact on the X02
pre-application. The contact PD/PI is strongly encouraged to continue the
multiple PD(s)/PI(s) leadership identified in the X02 pre-application if
notified of the opportunity to submit a UH3 application.

NIH Intramural Research Program (IRP) investigators are
eligible to apply for the UH3 FOA, subject to the availability of intramural
funds to support the project. IRP investigators can apply as PD(s)/PI(s), as multiple
PD/PIs in conjunction with extramural investigators (http://grants.nih.gov/grants/multi_pi/index.htm),
or as collaborators with extramural academic or biotechnology company
investigators. Intramural Research Investigators cannot request extramural
funds. For more information, see Section
6, Other Submission Requirements and Information.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an Application
Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Specific
Instructions for Preparing a UH3 Application

1. The selected Agent and new therapeutic use should be the
same as proposed in the X02 pre-application.

2. UH3 applications are limited to 12 pages for the Research
Strategy section including milestones, timeline and future plans.

3. See Section 6, Other Submission Requirements and Information
for additional information.

Specific
Aims

The one-page Specific Aims section should include the
following information:

1. Define the aims of the Phase IIa proof of concept clinical
trial.

a. The aims should include proposed clinical trials to
determine target modulation and efficacy.

b. The clinical data resulting from the UH3 component should
provide sufficient evidence that the drug candidate is safe and well-tolerated for
sustained administration in the proposed dose range, modulates the
target/mechanism and a biomarker of PD effect, and has a signal of efficacy in
the disease population.

Research
Strategy

Within the 12-page Research Strategy, provide the following
information:

1. Background
& Significance

a. Identify the Agent, its known pharmacologic mechanism of
action or target, and route of administration.

b. State the biological rationale or hypothesis for the new
therapeutic use of the Agent

c. Indicate the disease, clinical population, and public
health need that will be addressed by the proposed new use of the Agent.

1). Address the global burden of
disease, which patients will benefit, how they will benefit, how use of the
Agent will be superior to current therapy options, and potential for impact on
public health.

2. Preliminary
Studies

a. The Preliminary Studies will contain, but are not limited
to, data and information that validate the feasibility of conducting studies to
address the specific aims.

1). Evidence that the target or specific pathway is involved
in the disease pathology.

2). Any additional relevant information on the Agent (e.g.,
availability of pharmacokinetics (PK) and pharmacodynamics (PD) markers, any
exclusions or restrictions in the Agent's use).

3). Data to support the selection of dose and exposure of
the Agent based on available PD/PK biomarkers or functional pharmacological
activity.

4). Information on the risk/benefit of the Agent to patients
and the operational feasibility of conducting clinical trials to address the
specific aims.

3.
Approach

a. Describe and justify the design of the Phase IIa proof of
concept trial to assess activity of the Agent to change the disease state in
the proposed patient group.

1). Describe the use of PK and PD biomarkers, when
available, to select the dose and exposure of the Agent at the target site of
action, binding at the target, or expression of functional pharmacological
activity of the Agent at the target site of action.

2). Specify the duration of studies, based on safety data
available for the Agent, and whether the new use of the Agent is for treatment
of an acute or chronic disease.

3). Specify dose range, route of administration, and amount
of Agent needed based on the formulation available for the selected Agent.

Assess operational feasibility and resources needed: human
subjects protection approval and monitoring necessary to complete the work of
the UH3 (e.g., IND, IRB approval, Data and Safety Monitoring Plan approval),
access to and number of patients, patient selection criteria, availability of
the Agent, and formulation.

b. Provide a clear description of the timeline, interim
milestones and go/no decision points during the course of the clinical trial.

Enrollment rate (e.g., number of subjects meeting
eligibility criteria for enrollment per month, criteria for terminating the
study if minimum recruitment milestones are not met by the mid-point of the
study).

Futility analysis (e.g., what are the criteria for
conducting an interim analysis for futility, failure to separate from placebo).

c). Identify any impediments that could require an addendum
to the research plan, milestones, or timeline with a discussion of alternative
approaches.

d). Provide detailed quantitative criteria by which
milestone achievement will be assessed.

e). Provide a detailed timeline for the anticipated
attainment of each milestone and the overall goal.

5. Future
Plans

a. Describe the commercial potential of the Agent as a
development candidate and potential challenges for commercialization of the
Agent for the new disease indication.

The
following sections are not part of the Research Strategy but must be included
in the application:

Protection
of Human Subjects

Address Human Subjects protections for any clinical research
anticipated in the period of the grant, as described in the PHS 398 application
instructions. Human subjects protection should be detailed for the proposed Phase
IIa proof of concept trial. Describe in detail known information and possible
contingencies regarding potential risks and benefits to participation, and
plans to obtain informed consent. Include anticipated plans for data and
safety monitoring commensurate with potential risks inherent in Phase Ib and IIa
clinical trials.

Inclusion
of Women and Minorities, Inclusion of Children

Provide description of plans for adequate inclusion of
minorities and women in the clinical sample, or justify any exclusions.
Include a targeted/planned enrollment table for each of the planned studies
involving human subjects. Provide description of plans for adequate inclusion
of children in the clinical sample, or justify any exclusions. Inclusion plans
should be provided separately for each stage of the award.

Letters
of Support

Include a letter of support from the pharmaceutical company
partner documenting: access to the Agent and associated data needed for filing
an investigator-sponsored IND for the Agent to conduct the proposed clinical
trials (e.g., a letter indicating that a CRA has been executed, that the PD/PI
has the right to cross-reference specific sections of the pharmaceutical
company partner's IND/Drug Master File, etc.).

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide, with the following modifications:

All applications, regardless of the amount of direct costs
requested for any one year, should include a Data Sharing Plan.

Positive or negative data from NIH supported clinical trials
should be made available to the research community through ClinicalTrials.gov, publications, or public
website, consistent with achieving the goals of the Program. The applicant
should address a plan and timeline for sharing clinical trials data.

Appendix

Appendices are not allowed for this FOA and will not
be accepted. Do not use the other attachments section.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in
advance of the deadline to ensure they have time to make any application corrections
that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure accurate
and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD/PI Commons ID in the credential field will prevent the
successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by NCATS.
Applications that are incomplete and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to
notify the NCATS Referral Office by email at therapeutics.discovery@nih.gov when the application
has been submitted. Please include the FOA number and title, PD/PI name, and
title of the application:

Prior to funding an
application, the Program Official will contact the applicant to discuss the
proposed UH3 milestones and potential changes suggested by NIH staff or the NIH
review panel. The Program Official and the applicant will negotiate and
agree on a final set of approved UH3 milestones. These milestones will be
the basis for judging progress towards and completion of the interim milestones
in the UH3 stage.

Data and Safety
Monitoring

All NIH supported
clinical trials, including Phase I trials, require monitoring (NIH Guidance on
Data and Safety Monitoring for Phase I and Phase II Trials NOT-OD-00-038).
Although a general DSMP may be appropriate for the initial grant application,
NIH staff must review and approve a detailed DSMP with required supporting
material prior to the start of any trial. Early discussions with NIH staff are
encouraged to prevent delays. The proposed level of monitoring should be
commensurate with risk. For many studies, the grantee manages data and safety
monitoring. In specific cases, NIH may establish and manage independent data and
safety monitoring boards (DSMBs) for trials that utilize NIH grant resources.
For Phase IIa proof of concept trials, this level of monitoring may be
appropriate if the studies have multiple clinical sites, are blinded (masked),
or employ particularly high-risk interventions or vulnerable populations. In
these cases, NIH establishes a charter, appoints members and an executive
secretary, provides conflict of interest vetting, and supports the activities
of the DSMB. The NIH is responsible for continuing oversight even if
monitoring is delegated to the grantee. All other NIH Policies related to
clinical research, including trials, will also apply to the UH3 award.

Documentation
of access to the Agent proposed for use in the UH3 studies

Consistent with achieving
the goals of the Program, the applicant must provide the NIH with documentation
of access to the Agent, which was proposed in the X02 pre-application, and
associated data needed for conducting the proposed pre-clinical studies and for
filing an investigator-sponsored IND in order to conduct the proposed clinical trials
(e.g., an executed CRA or letter from the pharmaceutical partner).

Additional
Instructions for NIH Intramural Research Program (IRP) Applicants

1. IRP investigators
can apply as PD(s)/PI(s), as multiple PD(s)/PI(s) in conjunction with
extramural investigators (http://grants.nih.gov/grants/multi_pi/index.htm),
or as collaborators with extramural academic or biotechnology company
investigators, pending the availability of intramural funds to support the
project.

3. An official letter
from the Scientific Director, which indicates approval of the IRP scientist's
role as PD/PI or as collaborator in the project, must be included as a letter
of support in the UH3 application. The letter must specify the Scientific
Director's commitment of intramural research funds to support the IRP
investigator's proposed UH3 project or project component.

4. Justification must
be provided for all proposed personnel (Federal employees and contract staff)
who will be committing effort on the project although no funds are requested in
the application. Applicants should indicate the number of person-months
devoted to the project, even though no extramural funds are requested for
salary and fringe benefits.

5. If selected, NIH IRP scientists, in conjunction
with their respective technology transfer representative, will need to contact
the pharmaceutical company partner participating in this Program for the
selected Agent to: execute a CDA to exchange confidential information, and negotiate a PHS Cooperative Research and Development
Agreement (CRADA), Clinical Trials CRADA,
or other similar type of agreement, to incorporate, as appropriate, the terms
of the CRA.

6. If selected, NIH
intramural scientists will participate in this program as PD(s)/PI(s) in accord
with the Terms and Conditions provided in this FOA. Intellectual property will
be managed in accord with established policy of the NIH.

7. Should an
extramural application include the collaboration with an IRP scientist, no extramural
funds may be requested to support the IRP scientist or IRP laboratory.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115,

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field? Does the proposed project have the
potential for influence with regard to a new therapeutic use for the Agent in a
disease or disorder for which there is no current treatment or clinical
outcome, or for which the current standard of care has considerable
disadvantages or very limited utility? Is there a strong biological rationale
for the indicated therapeutic use?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD(s)/PI(s), do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project? What are the qualifications, experience, and commitment of the personnel involved in the
proposed therapeutics discovery project? Do the PD(s)/PI(s) have the scientific
and organizational vision and experience to serve effectively as the Director(s)
of the project? Is there evidence of sufficient management capabilities that
include fiscal administration, personnel management, planning, and budgeting?
Does the investigative team have the requisite competencies and experience with
clinical trials recruitment and execution? Do the PD(s)/PI(s) demonstrate relevant
experience and knowledge of the public-private partnerships?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed? What is the evidence for the biological hypothesis for the proposed new use of the
Agent (its pharmacologic mechanism of action or target) and relevance of the
biology to therapeutic intervention in the proposed disease that suggests
likelihood of successful completion of Phase IIa proof of concept trials during
the two-year project period? Are procedures in place for quality control and
quality assessment of the clinical procedures? Are data management and support
procedures developed sufficiently to allow tracking of clinical trial data? Have
the PD(s)/PI(s) provided an operational plan for managing the necessary
collaborations between and among clinical plan investigators and the
pharmaceutical company partner? Is a plan in place for timely submission of an
IND application for the clinical trial, expedited IRB review and approval, and timely
patient recruitment? What is the likelihood of the proposed project in meeting
the goals under the compressed two-year timeline of the FOA?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements? Are facilities adequate for the overall functions of the project
and to implement the goals of the program? Is there evidence for institutional
commitment to the program, including provision of space, and other measures of
institutional commitment? Are the research environment and resources, including
equipment and facilities, adequate? Does the scientific environment
indicate the potential for a multi-disciplinary approach involving teams of
investigators? Is a team in place to rapidly implement the proposed trial?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Milestones and Timeline

Are appropriate, evaluative milestones provided for
the UH3 stages clearly defined? Are the UH3 milestones feasible, well developed
and quantifiable with regard to the specific aims? Is the timeline feasible
for the UH3? Are the go/no go decision points, recruitment goals, and
timelines appropriate for the Phase IIa proof of concept trial in the UH3?

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign
Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor possession
use and transfer of Select Agent(s), and 4) plans for appropriate biosafety,
biocontainment, and security of the Select Agent(s).

Reviewers will also comment on whether the applicant
has addressed a plan and timeline for sharing positive or negative clinical trials
data (e.g., through ClinicalTrials.gov,
publications, or public website.

Budget and Period of Support

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s), convened by the NCATS, in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact/priority
score.

Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in
response to this FOA.

Applications will be assigned to NCATS with potential secondary assignment based on the proposed disease population to the
appropriate NIH Institute or Center. Applications will compete for available
funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive
a second level of review by the NCATS Advisory Council. The following will be
considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD(s)/PI(s) will be able to access his or her Summary Statement (written
critique) via the eRA Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH
Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

The following special terms of award are in addition to, and
not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB)
administrative guidelines, U.S. Department of Health and Human Services (DHHS)
grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is
applicable when State and local Governments are eligible to apply), and other
HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the
cooperative agreement, an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH programmatic
involvement with the awardees is anticipated during the performance of the
activities. Under the cooperative agreement, the NIH purpose is to support and
stimulate the recipients' activities by involvement in and otherwise working
jointly with the award recipients in a partnership role; it is not to assume
direction, prime responsibility, or a dominant role in the activities.
Consistent with this concept, the dominant role and prime responsibility
resides with the awardees for the project as a whole, although specific tasks
and activities may be shared among the awardees and the NIH as defined below.

The
PD(s)/PI(s) will have the primary responsibility for:

Determining the experimental research approaches, designing
protocols, setting project milestones and go/no go decision points, and
conducting the project within the guidelines of the FOA.

Submitting an investigator-sponsored IND, assuming responsibility
for the development, assembly, and submission of all required regulatory
documents, and providing all required information to NIH staff. This includes
but is not limited to all communications with the FDA (or other regulatory
authority) and the IRB.

Compliance with all federal regulations and NIH policies,
including those related to clinical research and clinical trials. Adherence to
NIH requirements for clinical trial monitoring, including oversight by an
independent NIH Data and Safety Monitoring Board (DSMB) if required by NIH.

Ensuring the timely submission of the clinical trial protocol,
consent form, and periodic reports for the project to the NIH as
required. Ensuring timely submission of all information and documents
required by NIH for oversight of the project and data and safety monitoring.

Submitting required documents, including adverse events or
unanticipated problems, to the FDA or OHRP in a timely manner as required by
regulation, and submitting these reports to NIH staff at the time of submission
to the appropriate agency.

Inviting external scientist(s) to serve as advisors on the
Steering Committee as needed, in consultation with the NIH Program Official,
NIH Project Scientist, and pharmaceutical company partner.

The PD(s)/PI(s) will chair the Steering Committee, organize and
circulate a written agenda in advance of conference calls and meetings, and
prepare and circulate minutes that delineate decisions and action items
resulting from the calls or meetings.

Adhering to Steering Committee policies and accepting the
participation and assistance of NIH staff in accordance with the guidelines
described in the NIH staff responsibilities in the Terms and Conditions of
Award.

Providing periodic reports to the Steering Committee summarizing:
the progress of the project; obstacles encountered and solutions; monthly
recruitment updates; and quarterly milestones updates. The reports should be
provided in a format decided upon by the Steering Committee.

Retaining custody of and have primary rights to the data and
software developed under these awards, subject to Government rights of access
consistent with current HHS, PHS, and NIH policies, consistent with the terms
of the CRA.

NIH
staff have substantial programmatic involvement that is above and beyond the
normal stewardship role in awards, as described below:

The Project Scientists will:

Have substantial scientific/programmatic involvement during
conduct of this cooperative agreement, through technical assistance, advice,
and coordination above and beyond normal program stewardship of grants.

Coordinate with the awardees in monitoring issues relating to: design
of the activities, recruitment, adherence to protocols, adjustment of study
protocols, and management and technical performance.

Participate in all Steering Committee activities, including
conference calls, subcommittees and special committees.

Participate in the review of clinical research protocols and data
safety monitoring plans, and depending on their level of complexity and risk,
recommend further review by the NIH DSMB or another monitoring body.

Participate in weekly project update meetings with the PD/PI.

The Program Official will:

Be responsible for the normal scientific and programmatic
stewardship of the award.

Participate in all Steering Committee meetings and conference
calls.

Monitor recruitment status of the trial on an ongoing basis.

Monitor performance through consideration of quarterly meetings
of the Steering Committee and annual reports, site visits, and compliance with
NIH procedures.

Approve modifications to the research plan and/or study
protocol(s), in consultation with the Steering Committee, based on emerging
data and/or other issues that impact progress of the project.

Determine if the awardee has met/achieved milestones for the
project.

Reserve the right to obtain periodic external peer review, and
recommend reviewers for, an assessment of progress and achievement of
milestones.

Reserve the right to terminate or curtail a UH3 project for any
of the following reasons: (1) inadequate progress in meeting the pre-negotiated
milestones and timelines; (2) risk to subject safety; (3) slow accrual; (4) data
from a futility analysis; or (5) failure to comply with the Terms and Conditions
of Award.

Areas
of Joint Responsibility include:

Steering
Committee:

Each awardee's project will have a Steering Committee. The
Steering Committee will serve as the operational governing board for the
project. The Steering Committee will include: the PD(s)/PI(s), key personnel,
the pharmaceutical company collaborator or consultant as an ex officio member,
the NIH Project Scientist, the NIH Program Official, and external scientist(s).

The Steering Committee will:

Participate in monitoring scientific progress of the UH3 research
project plan, assessing recruitment, progress of the go/no go milestones, and
assessing whether go/no go criteria have been met.

Convene quarterly meetings (in person or by video or audio
teleconference) to monitor progress on the research project plan and to address
issues or activities that impact the project. At least one in person meeting
should be held annually in the Washington, D.C. area to allow attendance of NIH
staff.

Hold teleconferences to address operational issues on a monthly
basis, or as dictated by the needs of the study.

Establish workgroups for specific tasks as the Steering Committee
deems appropriate. The workgroups will make recommendations to the Steering
Committee.

Ensure timely publication of abstracts and scientific articles to
make results of projects and inventions available, including negative data
regarding new therapeutic uses.

Participate in monitoring of intellectual property arising from
the project.

Dispute
Resolution:

Any disagreements that may arise in scientific or
programmatic matters (within the scope of the award) between award recipients
and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel
composed of three members will be convened. It will have three members: a
designee of the Steering Committee chosen without NIH staff voting, one NIH
designee, and a third designee with expertise in the relevant area who is
chosen by the other two; in the case of individual disagreement, the first
member may be chosen by the individual awardee. This special dispute resolution
procedure does not alter the awardee's right to appeal an adverse action that
is otherwise appealable in accordance with PHS regulation 42 CFR Part 50,
Subpart D and DHHS regulation 45 CFR Part 16.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH
Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH
Grants Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301, 479 and 480 of the Public Health Service Act as amended (42 USC 241, 287 and 287a)
and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.